rs930421180

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001142800.2(EYS):c.4045C>T(p.Arg1349*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,551,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.813

Publications

6 publications found

Variant links:

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

EYS Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 6-64591822-G-A is Pathogenic according to our data. Variant chr6-64591822-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.4045C>T	p.Arg1349*	stop_gained	Exon 26 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.4045C>T	p.Arg1349*	stop_gained	Exon 26 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.4045C>T	p.Arg1349*	stop_gained	Exon 26 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.4045C>T	p.Arg1349*	stop_gained	Exon 26 of 44	ENSP00000359655.3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1399070

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

690044

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31576

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000222

AC:

AN:

1078726

Other (OTH)

AF:

0.0000172

AC:

AN:

57994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000325

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg1349*) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 24265693, 28041643). ClinVar contains an entry for this variant (Variation ID: 438197). For these reasons, this variant has been classified as Pathogenic.

Aug 22, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35046417, 24265693, 28041643, 30337596, 31054281, 32581362, 31589614, 31074760, 32531858)

Retinitis pigmentosa 25

Pathogenic:4

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 06, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 26, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa

Pathogenic:3

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EYS c.4045C>T (p.Arg1349X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.2e-05 in 31404 control chromosomes. c.4045C>T has been reported in the literature in mulitple individuals affected with Retinitis Pigmentosa (e.g., Weisschuh_2020). The following publication have been ascertained in the context of this evaluation (PMID: 32531858). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Retinal dystrophy

Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.15

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.11

PhyloP100

0.81

Vest4

0.70

GERP RS

3.0

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over